Tumor-secreted IFI35 promotes proliferation and cytotoxic activity of CD8+ T cells through PI3K/AKT/mTOR signaling pathway in colorectal cancer.

BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. METHODS: Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. RESULTS: The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells.

Comparative Safety, Efficacy and Survival Outcome of Anti-PD-1 Immunotherapy in Colorectal Cancer Patients With vs Without Hepatitis B Virus Infection: A Multicenter Cohort Study.

INTRODUCTION: Antiprogrammed cell death protein-1 (PD-1) immunotherapy has substantially broadened in scope for the treatment of colorectal cancer (CRC). However, comparative safety, efficacy and survival outcome of anti-PD-1 therapy in CRC patients with and without hepatitis B virus (HBV) infection remain unclear. METHODS: This multicenter, retrospective cohort study included 180 advanced-stage CRC patients with available serological markers for HBV infection treated with anti-PD-1 therapy at the Sixth Affiliated Hospital, Sun Yat-sen University and Sun Yat-sen University Cancer Center between December 2016 and December 2019. A propensity score-matched analysis was performed to compare the safety, efficacy, and survival outcome between HBV and non-HBV groups. RESULTS: The incidences of deficient mismatch repair and metastatic disease were significantly different between HBV and non-HBV groups (both P < 0.05). After propensity score-matched analysis, any grade immune-related adverse events and grade ≥ 3 immune-related adverse events were 47% vs 38% (P = 0.25) and 5% vs 6% (P = 1.0) between HBV and non-HBV groups, respectively. The overall response rate was 39% with 17 complete responses and 13 partial responses for the HBV infection cohort and 39% with 11 complete responses and 19 partial responses for the non-HBV infection cohort (P = 1.0). Two-year progression-free survival rates were 38% vs 40% (P = 0.596) and 2-year overall survival rates were 55% vs 63% (P = 0.401) for HBV vs non-HBV infection cohorts. DISCUSSION: The incidences of toxicity, efficacy and survival outcome were similar between patients with HBV infection and non-HBV patients receiving anti-PD-1 therapy, which supports to include CRC patients with HBV in clinical trials of anti-PD-1 therapy.

Association of Peripheral Blood Biomarkers With Response to Anti-PD-1 Immunotherapy for Patients With Deficient Mismatch Repair Metastatic Colorectal Cancer: A Multicenter Cohort Study.

Purpose: Deficient mismatch repair (dMMR) is an established biomarker for the response to the programmed cell death (PD)-1 inhibitors in metastatic colorectal cancer (mCRC). Although patients with dMMR mCRC could achieve a high incidence of disease control and favorable progression-free survival (PFS), reported response rates to PD-1 inhibitors are variable from 28% to 52%. We aimed to explore the additional predictive biomarkers associated with response to anti-PD-1 immunotherapy in patients with dMMR mCRC. Methods: This multicenter cohort study enrolled patients with dMMR mCRC receiving anti-PD-1 immunotherapy at the Sixth Affiliated Hospital of Sun Yat-sen University and Sun Yat-sen University Cancer Center between December 2016 and December 2019. The total information of 20 peripheral blood biomarkers, including T cells (frequency of CD4+ T cell, frequency of CD8+ T cell, and ratio of CD4+/CD8+), carcinoembryonic antigen (CEA), inflammatory markers, and lipid metabolism markers, was collected. The association between response or survival and peripheral blood parameters was analyzed. Results: Among the tested parameters, the ratio of CD4+/CD8+ and frequency of CD4+ T cell were significantly associated with PFS (p = 0.023, p = 0.012) and overall survival (OS; p = 0.027, p = 0.019) in a univariate analysis. A lower level of CD4+/CD8+ ratio or frequency of CD4+ T cell showed a significant association with better overall response rates (ORRs; p = 0.03, p = 0.01). The ratio of CD4+/CD8+ and frequency of CD4+ T cell maintained significance in multivariate Cox model for PFS (HR = 9.23, p = 0.004; HR = 4.83, p = 0.02) and OS (HR = 15.22, p = 0.009; HR = 16.21, p = 0.025). Conclusion: This study indicated that the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might be crucial independent biomarkers within dMMR mCRC to better identify patients for anti-PD-1 immunotherapy. If validated in prospective clinical trials, the ratio of CD4+/CD8+ and the frequency of CD4+ T cell might aid in guiding the treatment of PD-1 inhibitors among patients with dMMR mCRC.